Purified Hydroxypropyl Beta-Cyclodextrin for Chronic CNS Dosing
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Solution Overview
Problem
Current hydroxypropyl beta-cyclodextrin compositions used for treating Niemann-Pick disease contain impurities like propylene glycol, beta-cyclodextrin molecules with no hydroxypropyl substitutions, and bacterial endotoxin, making them unsuitable for chronic intrathecal or intracerebroventricular administration, and their complex mixtures lack precise compositional control.
Innovation Solution
Development of a pharmaceutical composition with a controlled mixture of beta-cyclodextrin molecules having specific degrees of hydroxypropyl substitution, reduced impurities, and improved purity, suitable for intrathecal or intracerebroventricular administration, achieved through methods such as absorption chromatography and solvent precipitation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If hydroxypropyl beta-cyclodextrin compositions are used for treating Niemann-Pick disease, then therapeutic benefits are achieved, but impurities (propylene glycol, unsubstituted beta-cyclodextrin molecules, bacterial endotoxin) make them unsuitable for chronic intrathecal or intracerebroventricular administration
Solution Approach 1:
The patent applies extraction by removing impurities (propylene glycol, unsubstituted beta-cyclodextrin molecules, and bacterial endotoxin) from the hydroxypropyl beta-cyclodextrin composition through purification processes, thereby making the composition suitable for chronic intrathecal or intracerebroventricular administration while retaining the therapeutic benefits
Solution Approach 2:
The patent changes the compositional parameters of the hydroxypropyl beta-cyclodextrin by controlling the degree of hydroxypropyl substitution and specifying precise ratios of substituted versus unsubstituted molecules, thereby transforming the composition from an impure form to a purified pharmaceutical grade suitable for chronic CNS administration
2Reliability
If complex mixtures of hydroxypropyl beta-cyclodextrin are used, then therapeutic effects are observed, but precise compositional control is lacking
Solution Approach 1:
The patent specifies precise compositional parameters including the degree of hydroxypropyl substitution (DS) and the ratio of substituted to unsubstituted beta-cyclodextrin molecules, thereby achieving manufacturing precision while maintaining therapeutic efficacy through controlled composition rather than complex mixtures
Solution Approach 2:
The patent applies local quality by specifying different proportions of hydroxypropyl-substituted beta-cyclodextrin molecules (with DS of 3, 4, 5, 6, or 7) versus unsubstituted molecules in the composition, allowing precise control over the therapeutic properties while maintaining efficacy through defined quality parameters
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The purified composition provides therapeutic benefits for Niemann-Pick disease with reduced side effects and improved safety, allowing for longer and more frequent dosing without adverse reactions.
Implementation Method 1
2-Hydroxypropyl-beta-cyclodextrins have been shown to alleviate excess cholesterol storage in NPC cells, consistent with a previous report of related cyclodextrins extracting cholesterol from the plasma membrane of cells
Implementation Method 2
achieved through methods like absorption chromatography and solvent precipitation
Implementation Method 3
achieved through methods like absorption chromatography and solvent precipitation
Data Source
AI summary
This disclosure provides mixtures of beta-cyclodextrin molecules substituted at one or more hydroxyl positions by hydroxypropyl groups, the mixture optionally including unsubstituted beta-cyclodextrin molecules, for use as a pharmaceutically active ingredient; methods of making such mixtures; methods of qualifying such mixtures for use in a pharmaceutical composition suitable for intrathecal or intracerebroventricular administration; pharmaceutical compositions suitable for intrathecal or intracerebroventricular administration comprising such mixtures; and methods of using the pharmaceutical compositions for treatment of Niemann-Pick disease Type C.